Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer's disease.

Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer's disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aβ is untested. Here, we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aβ in the human brain and play a key role in promoting abnormal neuronal hyperactivity in an AD knock-in mouse model. We show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in the mouse model in vivo.

Characterisation of early ultrastructural changes in the cerebral white matter of CADASIL small vessel disease using high-pressure freezing/freeze-substitution.

Aims: The objective of this study was to elucidate the early white matter changes in CADASIL small vessel disease.

Methods: We used high-pressure freezing and freeze substitution (HPF/FS) in combination with high-resolution electron microscopy (EM), immunohistochemistry and confocal microscopy of brain specimens from control and CADASIL (TgNotch3 ) mice aged 4-15 months to study white matter lesions in the corpus callosum.

Results: We first optimised the HPF/FS protocol in which samples were chemically prefixed, frozen in a sample carrier filled with 20% polyvinylpyrrolidone and freeze-substituted in a cocktail of tannic acid, osmium tetroxide and uranyl acetate dissolved in acetone.

A Vessel for Change: Endothelial Dysfunction in Cerebral Small Vessel Disease.

The blood vessels of the brain are lined with endothelial cells and it has been long known that these help to regulate blood flow to the brain. However, there is increasing evidence that these cells also interact with the surrounding brain tissue. These interactions change when the endothelial cells become dysfunctional and have an impact in diseases such as cerebral small vessel disease, the leading cause of vascular dementia.

Blood brain barrier leakage is not a consistent feature of white matter lesions in CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a genetic paradigm of small vessel disease (SVD) caused by NOTCH3 mutations that stereotypically lead to the vascular accumulation of NOTCH3 around smooth muscle cells and pericytes. White matter (WM) lesions (WMLs) are the earliest and most frequent abnormalities, and can be associated with lacunar infarcts and enlarged perivascular spaces (ePVS). The prevailing view is that blood brain barrier (BBB) leakage, possibly mediated by pericyte deficiency, plays a pivotal role in the formation of WMLs.

Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats.

Dementia is a major social and economic problem for our aging population. One of the most common of dementia in the elderly is cerebral small vessel disease (SVD). Magnetic resonance scans of SVD patients typically show white matter abnormalities, but we do not understand the mechanistic pathological link between blood vessels and white matter myelin damage.

Endothelial cell-oligodendrocyte interactions in small vessel disease and aging.

Cerebral small vessel disease (SVD) is a prevalent, neurological disease that significantly increases the risk of stroke and dementia. The main pathological changes are vascular, in the form of lipohyalinosis and arteriosclerosis, and in the white matter (WM), in the form of WM lesions. Despite this, it is unclear to what extent the key cell types involved-the endothelial cells (ECs) of the vasculature and the oligodendrocytes of the WM-interact.